Blood vessels can adjust to altered hemodynamic situations by changing their diameter. For example, a reduction or cessation of blood flow through the common carotid artery leads to constrictive remodeling of the vessel with a decrease in total cross-sectional vessel area and a decrease in lumen area. Conversely, during the development of atherosclerotic plaques in arteries a loss of lumen area is initially counteracted via the process of outward remodeling of the vessel, so that the lumen area can be maintained despite an increase in plaque volume.
However, with continued plaque growth in coronary heart disease and peripheral vascular disease there is limited ability for compensatory outward remodeling of the vessel. Thus, the vessel lumen decreases and tissue perfusion decreases. Many approaches including those using angiogenic growth factors to promote vascularization of ischemic tissues have failed in clinical trials.
Heart failure is a consequence of impaired cardiac function and therapeutic options to improve cardiac performance are limited. Most inotropic factors also increase heart rate thereby increasing the oxygen requirements of the myocardium, which can exacerbate existing ischemic conditions even further. Agents that can promote cardiac perfusion and increase contractile performance without affecting heart rate would be highly desirable from a therapeutic point of view.
Thus, there is a need to develop safe and efficacious approaches for the treatment of coronary heart disease, peripheral vascular disease, and cardiac failure.